title: Systemic disease during Streptococcus pneumoniae acute lung infection requires 12-lipoxygenase-dependent inflammation.
abstract: Acute pulmonary infection by Streptococcus pneumoniae is characterized by high bacterial numbers in the lung, a robust alveolar influx of polymorphonuclear cells (PMNs), and a risk of systemic spread of the bacterium. We investigated host mediators of S. pneumoniae-induced PMN migration and the role of inflammation in septicemia following pneumococcal lung infection. Hepoxilin A3 (HXA3) is a PMN chemoattractant and a metabolite of the 12-lipoxygenase (12-LOX) pathway. We observed that S. pneumoniae infection induced the production of 12-LOX in cultured pulmonary epithelium and in the lungs of infected mice. Inhibition of the 12-LOX pathway prevented pathogen-induced PMN transepithelial migration in vitro and dramatically reduced lung inflammation upon high-dose pulmonary challenge with S. pneumoniae in vivo, thus implicating HXA3 in pneumococcus-induced pulmonary inflammation. PMN basolateral-to-apical transmigration in vitro significantly increased apical-to-basolateral transepithelial migration of bacteria. Mice suppressed in the expression of 12-LOX exhibited little or no bacteremia and survived an otherwise lethal pulmonary challenge. Our data suggest that pneumococcal pulmonary inflammation is required for high-level bacteremia and systemic infection, partly by disrupting lung epithelium through 12-LOX-dependent HXA3 production and subsequent PMN transepithelial migration.
authors.affiliation: Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111, USA.
authors.forename: Rudra
authors.initials: R
authors.lastname: Bhowmick
authors.affiliation: Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nang
authors.initials: N
authors.lastname: Maung
authors.affiliation: Mucosal Immunology Laboratory, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Hurley
authors.affiliation: Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111, USA.
authors.forename: Elsa Bou
authors.initials: EB
authors.lastname: Ghanem
authors.affiliation: Vision Science Program, School of Optometry, University of California, Berkeley, CA 94720, USA.
authors.forename: Karsten
authors.initials: K
authors.lastname: Gronert
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: McCormick
authors.affiliation: Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Leong
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000276:immunology / Q000378:metabolism*; D001412:Bacillus subtilis; D016470:Bacteremia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002630:Chemotactic Factors / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D008171:Lung Diseases / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D011008:Pneumococcal Infections / Q000276:immunology* / Q000473:pathology; D013296:Streptococcus pneumoniae / Q000472:pathogenicity; D057705:Transendothelial and Transepithelial Migration
chemical_list: D002630:Chemotactic Factors; C038243:8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid; D001092:Arachidonate 12-Lipoxygenase; D015126:8,11,14-Eicosatrienoic Acid